Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Survival has steadily improved over the last twenty years with widespread use of autologous stem cell transplantation (ASCT) and the development of potent anti-myeloma drugs. Up to 30% of patients now attain complete responses (CR). However, even for patients who attain CR, relapse is inevitable. Progress towards a cure for multiple myeloma therefore requires methods to sensitively measure the minimal residual disease (MRD) that leads to relapse in patients who achieve CR. Such methods should allow frequent and non-invasive MRD tracking so that therapy can be titrated to the deepest possible remissions. To address this unmet need, we propose to validate high-throughput sequencing of immunoglobulin genes (Ig HTS) as a non-invasive peripheral blood assay for MRD assessment in multiple myeloma. Several studies have demonstrated the prognostic value of MRD assessment in patients in CR after ASCT using flow cytometry, allele-specific PCR, and Ig HTS. However, these studies relied on analysis of bone marrow samples from patients treated with now-obsolete regimens. Our proposed study would advance the field by being the first to assess the prognostic value of MRD using a peripheral blood assay and to do so in patients treated with modern regimens. We will use peripheral blood and bone marrow samples and clinical data from the 750-patient BMT-CTN 0702 trial, which compared three post-ASCT treatment strategies and recently completed accrual. Ig HTS is ideal for our study because it is more sensitive than flow cytometry and requires no custom design of patient-specific assays. Ig HTS tracks MRD by probing for the unique immunoglobulin gene sequence that distinguishes the malignant plasma cell clone in each patient from normal B cells and plasma cells. In this study we will: 1) determine the prognostic value of MRD assessment in the peripheral blood with Ig HTS and 2) determine if features of the reconstituting non-malignant immune repertoire post ASCT are predictive of progression-free survival (PFS). These analyses will inform the design of future studies in which post-ASCT maintenance therapy is personalized to MRD status to attain the best possible PFS with the least toxicity and cost. The use of a validated Ig HTS MRD assay on peripheral blood will also facilitate studies in which MRD status is used as a surrogate endpoint for evaluating novel post-ASCT therapies. Finally, these analyses will also yield novel insights into the biology of post-ASCT immune reconstitution and potentially yield new candidate biomarkers of response to post-ASCT multiple myeloma therapy.